Seerden Jean-Paul G, Leusink-Ionescu Gabriela, Woudenberg-Vrenken Titia, Dros Bas, Molema Grietje, Kamps Jan A A M, Kellogg Richard M
Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3412-8. doi: 10.1016/j.bmcl.2014.05.080. Epub 2014 Jun 2.
The synthesis and structure-activity relationships of novel 4-(4'-fluorophenyl)imidazoles as selective p38α MAPK, CK1δ and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38α MAPK with IC50=250 nM and 96 nM, respectively. Pyridine 3 gave CK1δ inhibition with IC50=89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50=62 nM.
本文描述了具有改善水溶性的新型4-(4'-氟苯基)咪唑作为选择性p38α丝裂原活化蛋白激酶（MAPK）、细胞周期蛋白依赖性激酶1δ（CK1δ）和Janus激酶2（JAK2）抑制剂的合成及其构效关系。微波辅助多组分反应得到4-氟苯基-2,5-二取代咪唑。通过“点击”反应引入羧酸盐和膦酸盐基团。激酶选择性受咪唑C-5处的杂芳基以及咪唑C-2处羧酸或四唑的位置影响。例如，嘧啶15和34分别以IC50 = 250 nM和96 nM抑制p38α MAPK。吡啶3对CK1δ的抑制作用IC50 = 89 nM，吡啶-2-酮31对JAK2的抑制作用IC50 = 62 nM。
